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Simultaneous EGF receptor and thrombin receptor activation synergistically induces pro‐angiogenic immediate early genes in endothelial cells
Author(s) -
Waitkus Matthew,
Chandrasekharan Unni,
DiCorleto Paul
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.575.4
Subject(s) - microbiology and biotechnology , receptor tyrosine kinase , transactivation , receptor protein tyrosine kinases , receptor , g protein coupled receptor , protease activated receptor , protease activated receptor 2 , signal transduction , biology , epidermal growth factor receptor , tropomyosin receptor kinase c , cancer research , growth factor receptor , platelet derived growth factor receptor , tyrosine kinase , chemistry , thrombin , 5 ht5a receptor , growth factor , transcription factor , biochemistry , immunology , gene , platelet
Signaling interactions between G‐protein coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) function in a number of pathophysiological processes, including cellular proliferation, invasion, and acquired resistance to chemotherapeutic agents. Here, we examine the consequences of simultaneous EGF receptor (EGFR) and thrombin receptor (protease‐activated receptor‐1, PAR‐1) activation in human endothelial cells (EC). We observe that concurrent EGFR and PAR‐1 activation causes the synergistic induction of at least six pro‐angiogenic immediate early genes (IEGs), including the transcription factor early growth response‐1 (EGR‐1). In contrast to other cell types, matrix metalloprotease‐mediated transactivation of EGFR by PAR‐1 does not appear to be a major signaling mechanism in EC. Instead, an intracellular mechanism involving glycogen synthase kinase‐3 (GSK‐3α/β) mediates receptor crosstalk by integrating signals from EGFR and PAR‐1. These findings provide a mechanistic basis for how cells integrate information of concurrent receptor activation to enhance EGR‐1 expression in EC. This study was supported by grant HL29582 from the National Institutes of Health (Dr. DiCorleto).